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Endometrial reseptivite arttırılabilir mi?

Endometrial reseptivite arttırılabilir mi?. Doç Dr Münire ERMAN AKAR Akdeniz Üniversitesi Kadın Hastalıkları ve Doğum AD ANTALYA. Implantation is a complicated process that requires the orchestration of a series of events involving both the embryo and the endometrium.

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Endometrial reseptivite arttırılabilir mi?

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  1. Endometrial reseptivite arttırılabilir mi? Doç Dr Münire ERMAN AKAR Akdeniz Üniversitesi Kadın Hastalıkları ve Doğum AD ANTALYA

  2. Implantation is a complicated process that requires the orchestration of a series of events involving both the embryo and the endometrium.

  3. Başarılı implantasyon için önemli faktörler • Embryo kalitesi • Endometrial reseptivite • Embryo gelişimi ve endometrial çevredeki değişiklikler arasında senkronizasyon

  4. INVASION MMP MMP IGFBP-1 LIF MCSF IL-4 Il-1 LIF Up regulation of -Phosphorylation -Decidualization -Differentiation PROGESTERONE GnRH CG

  5. The endometrium becomes receptive to blastocyst implantation 6–8 days after ovulation and remains receptive for 4 days (cycle days 20–24) (Bergh and Navot, 1992). • The importance of endometrial environment is highlighted by the observation that high-quality embryos transferred into women involved as embryo recipients in a surrogacy procedure have a higher probability of implanting than if they are transferred back into the donor women (Check et al., 1992; Stafford-Bell and Copeland,2001). • Poor embryo quality has also been identified as a major cause of implantation failure (Urman et al., 2005).

  6. Implantasyon üç ardışık fazdan oluşur: • Apposition • Attachment • Invasion

  7. Implantasyon reseptivitesi için biomarkırlar • Pinopodlar • Sitokinler ve büyüme faktörleri • Hücre adezyon molekülleri -Musin -Integrinler *luteal fazda alpha1 beta1 ,alpha4 beta1 ve alpha v beta3 endometrium ekspresyonu • Endometrial reseptivite için olası belirteçler -Hox genleri -kalsitonin • Lektinler

  8. DNA microarrays enable analysis of the simultaneous expression of thousands of genes in a single sample. • Possibly, gene expression may be a better marker of the biological phases and may be a more reliable predictor of endometrial receptivity than morphology. • To date, five studies have examined changes in endometrial gene expression during the receptive phase and all have reported genes that are strongly up(osteopontin)- or down-regulated when the endometrium is receptive . • Carson et al., 2002; Kao et al., 2002; Borthwick et al., 2003; Riesewijk et al., 2003; Mirkin et al., 2005

  9. Reseptivite arttırılabilir mi?

  10. Embryo transfer tekniği Servikal manipulasyon uterin kontraksiyonlarda artışa sebep olarak embryoların uterin kaviteden atılmasına sebep olur. Fanchin et al.,1998

  11. sert vs yumuşak embryo transfer kateterleri • 2006 tarihli bir meta-analizde • Sert ile yumuşak embryo transfer kateterinin karşılaştırıldığı 7 randomize kontrollü çalışmada yumuşak kataterle daha yüksek gebelik oranları elde edilmiştir (odds ratio(OR) 1.34, 95% confidence intervals(CI)1,18-1,54) (Buckett,2006)

  12. Geleneksel olarak, IVF sonrası embryo transferinde amaç uterin fundusun 1 cm altına transfer yapmaktır. • (Schoolcraft, 2001)

  13. Embryoların depozisyonu • Embryo transferinin endometrial kavite ortasına uygulandığı bir çalışmada daha iyi gebelik sonuçları elde edilmiştir (Oliveira et al.,2004) • Embryoların fundustan 1,5-2 cm altına verildiği olgularda 1 cm altına verilen olgulara göre daha yüksek implantasyon oranları bildirilmiştir. (Coroleu et al.,2002) • Fundustan her 1 mm uzağa transferde klinik gebelik oranının %11 arttığı tespit edilmiştir(Pope et al.,2004)

  14. USG’nın rolü • Dört randomize kontrollü çalışmanın metaanalizde ultrason rehberliğinde embryo transferiyle daha yüksek gebelik ve implantasyon oranları bildirilmiştir (1,38 , 95% CI 1,20-1,60) • (Buckett,2003)

  15. 3D ultrasound and power Doppler angiography on the day of hCG may be useful to assess endometrial receptivity in IVF-ICSI cycles when only one embryo is transferred(EV, VFI higher in the pregnant) • Merce et al 2008

  16. Bakterial vajinoziskolonizasyonu • Embryo transferi sırasında, serviksten uterin kaviteye bakteri invazyonu olabilir • IVF yapılan hastalarda % 25 oranında bakterial vaginosis prevalansı • Liversedge et al.,1999

  17. Prensipler • Uterin kavitenin dikkatli değerlendirilmesi • Hidrosalpenks varlığında salpenjektomi(Daftary et al 2007 endometrial HOXA10 ekspresyonu artar) • Uterin kontraktiliteden kaçınılması • Servikal mukusun aspire edilmesi, transfer öncesi genital kültür • Embryoların ultrason eşliğinde doğru yere transfer edilmesi • Transfer sonrası kataterin embryo retansiyonu açısından kontrol edilmesi

  18. Endometrial coculture • Blasomer sayısında artış • İmplantasyon oranında artış • Klinik ve devam eden gebelik oranlarında artış • Kattal et al(meta analiz), Fertil Steril 2008

  19. Adjuvan farmasitik tedavi

  20. Aspirin

  21. Randomized controlled trials investigating the use of aspirin as an empirical therapy in non-selected IVF populations.

  22. Clinical pregnancy (CP) rate per embryo transfer (ET) was not • found to be significantly different between patients who • received low-dose aspirin and those who received placebo • or no treatment (RR 1.09 95% CI 0.92-1.29). • On the basis of up-to-date evidence, low-dose aspirin has no substantial positive effect on likelihood of pregnancy for women undergoing IVF/ICSI. Low-dose aspirin for in vitro fertilization: a systematic review and meta-analysis T.A.Gelbaya et al., human reproduction, 2007

  23. Forest plot of the effect of aspirin versus placebo or no treatment on clinical pregnancy rate per embryo transfer. Review: aspirin versus nothing in IVF. Comparison: aspirin versus placebo or no treatment. Outcome: clinical pregnancy/embryo transfer.

  24. Forest plot of the effect of aspirin versus placebo or no treatment on miscarriage rate per clinical pregnancy. Review: aspirin versus nothing in IVF. Comparison: aspirin versus placebo or no treatment. Outcome: miscarriage/clinical pregnancy.

  25. Main results of the two RCTs comparing aspirin versus placebo in poor responders (Lok et al., 2004, Fratterelli 2008) or oocytes recipients (Weckstein et al., 1997)

  26. Nitrik oksit donorleri

  27. Effect of vaginal sildenafil on the outcome of in vitro fertilization(IVF) after multiple IVF failures attributed to poor endometrial development Geoffrey S. et al.,Fertility Sterility,2002

  28. Although subgroups of women may be identified who benefit from NO donor therapy, at present the available data demand caution in its use, which at present the available data demand caution in its use, which at present should be restricted to well-designed studies.

  29. Aromatase inhibitors Lowering supraphysiological estrogen levels Reducing gonadotropins requirements for optimum ovarian stimulation Mitwally MFM et al 2005

  30. Ascorbic acid • Ascorbic acid appears to be involved in normal folliculogenesis (Luck et al.,1995), ovulation (Igarashi,1977) and luteal formation and regression (Luck and Zhao,1993). • An imbalance of oxidative stress and antioxidant defence has been implicated in the pathogenesis of several diseases, including recurrent abortion, unexplained infertility and defective embryo development. • However, a RCT investigating the effect of 1,5 or 10 mg of ascorbic acid versus a placebo during the luteal phase in 620 women undergoing IVF showed no difference in implantation rates (Griesinger et al.,2002).

  31. Prolonged progesterone An important regulator of endometrium receptivity is the corpus luteum, the primary function of which is the production of progesterone.

  32. The optimal duration of progesterone administration remains to be clarified. • Many centers continue with progesterone supplementation throughout the first trimester of pregnancy. • However, the rationale for this approach is unclear. Proponents point to the uterine relaxing properties of progesterone, elegantly demonstrated by a reported negative correlation between uterine contractility frequency and progesterone concentrations • Fanchin et al.,1998)

  33. Secondly, progesterone has been shown to have potentially beneficial immunomodulatory properties. • Studies in mice demonstrated that progesterone administration abrogated the abortigenic effects of stress exposure by decreasing the frequency of Th1 cytokines • Blois et al., 2004 • Previous studies suggested that succesful pregnancy is more likely when Th2 rather than Th1 cytokines are predominant • Wegmann et al., 1993

  34. Although supplementation of progesterone is widely used to improve implantation rates, the application of luteal ESTRADIOL supplementation remains controversial. • A meta-analysis of three RCT (Smitz et al., 1993; Lewin et al.,1994; Farhi et al.,2000) using a long GnRH agonist protocol, reported no difference in pregnancy rates when oestrogen was added to progesterone in the luteal phase Pritts and Atwood,2002 • In contrast, a recent RCT of 166 women undergoing ICSI reported significantly higher pregnancy and implantation rates after oestradiol supplementation • Lukaszuk et al.,2005

  35. Glucocorticoids • Uterine receptivity is controlled by locally acting growth factors, cytokines and uterine natural killer (uNK) cells (Dey et al.,2004). It has been shown that uNK cells may have an important role in early implantation, since they accumulate around arteries supplying the implantation site (Croy et al.,2002). • A defect in the integrity of the number of uNK cells has also been implicated in implantation failure. Ledee-Batailie et al. reported higher numbers of NK cells in endometrial biopsies from women with implantation failure versus fertile controls (Ledee-Bataille et al.,2005). • An RCT of 206 patients, investigating the use of glucocorticoids from oocyte retrieval onwards, reported no differences in embryo implantation or pregnancy rates (Moffitt et al.,1995). These results are in line with another RCT addressing the effect of adjuvant glucocorticoids (Mottia et al.,2005).

  36. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles • Thirteen studies (1759 couples) were included. • Overall, there is no clear evidence that administration of peri-implantation glucocorticoids in ART cycles significantly improves clinical outcome. • The use of glucocortcoids in women undergoing IVF (rather than ICSI) was associated with an improvement in pregnancy rates of borderline statistical significance. • Boomsma C. et al., cochrane dtabase syst rev, 2007

  37. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial • IVIG did not improve the live-birth rate in couples with repeated unexplained IVF failure, stringently defined by known determinants of IVF outcome. • Mary D. S. et al.,Fertility and Sterility, 2000

  38. Insulin sensitizing drugs

  39. A meta-analysis of eight RCT investigating metformin in women with PCOS demonstrated no significant differences in pregnancy rates, although the risk of ovarian hyperstimulation syndrome (OHSS) was significantly reduced by metformin (Costeilo et al., 2006). • One recent RCT of 101 women with PCOS undergoing IVF, included in this meta-analysis, demonstrated lower rates of miscarriage and OHSS in the group receiving metformin (Tang et al.,2006).

  40. GnRH agonist The GnRH agonist group showed significantly higher endometrial thickness and higher pregnancy rate, suggestive of a higher endometrial receptivity, compared with the GnRH antagonist group Orvieto R,2008

  41. GnRH antagonist • HOXA10 expression was significantly decreased in endometrial stromal cells in GnRH antagonist-treated cycles compared with GnRH agonist-treated cycles or natural cycle control subjects • Rackow BW et al, 2008

  42. Assisted hatching on assisted conception (IVF & ICSI) • Objectives: to determine whether assisted hatching (ah) of embryos facilitates live births and clinical pregnancy and whether it impacts on negative outcomes (such as multiple pregnancy and miscarriage) • Results: twenty-three randomised controlled trials consisting of 2668 women reported on 849 pregnancy outcomes • Conclusions: despite significantly improved odds of clinical pregnancy, there is insufficient evidence to determine any effect of AH on live birth rates. The increased multiple pregnancy rate is of concern although it likely that with a policy of single embryo transfer this may be lowered. Currently, there is insufficient evidence to recommend assisted hatching. Seif MM, Edi-Osagie EC. et al., cochrane database syst rev, 2005

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